Determination of lipid dysregulation by per- and polyfluorinated alkyl substances (PFAS) in aquatic macroinvertebrates

Per- and polyfluorinated alkyl substances (PFAS) encompass a broad suite of chemicals which have been estimated to include 4,730 unique chemicals, with larger estimates placing this number at 14,735 different structures. Per- and polyfluorinated alkyl substances (PFAS) encompass a broad suite of chemicals which have been estimated to include 4,730 unique chemicals, with larger estimates placing this number at 14,735 different structures. The widespread contamination of the environment with these chemicals has been linked to multiple effects in humans such as cancer, thyroid disease, liver damage and decreased fertility. Recent research has also demonstrated adverse effects in animal health associated with metabolism, immune function, endocrine disruption and neurodevelopment. Whilst effects have been observed the underlying mechanisms that link cause to effect are lacking and remains a significant knowledge gap concerning PFAS exposures including the uptake and membrane transport behaviours. The accumulation of PFAS has the potential to disrupt lipid metabolism with evidence suggesting dysfunction in lipolysis, beta-oxidation with further consequences for glucose metabolism. Metabolism is a critical part of normal physiological function and homeostatic control and by analysing the metabolome it can provide a molecular fingerprint that is phenotypically anchored to reveal mechanisms behind cause-effect relationships. Moreover, mixture composition of PFAS can trigger different types of toxicities which further complicates effect-based studies and will require novel in-depth molecular approaches to delineate the toxicological outcomes. The aim of this project will be to determine the exposure of PFAS chemicals in freshwater macroinvertebrates to characterise metabolic dysfunction using lipidomics. The aim will be achieved through surveillance of PFAS chemicals present in the UK environment using targeted and non-target mass spectrometry. Organisms will then be exposed under controlled laboratory conditions to single and combinations of several relevant PFAS chemicals to determine alterations in lipid metabolism. Determination of molecular pathways linked to PFAS exposure will be developed into causal biological networks that will address knowledge gaps concerning toxicological outcomes.